We hypothesize that soluble amyloid beta-protein (Abeta) oligomers are key effectors of neurotoxicity and[unreadable] may be a primary cause of Alzheimer's disease (AD). Consequently, inhibition of Abeta Oligomerization[unreadable] is an attractive strategy for preventing and treating AD. We propose to use a systematic, rational[unreadable] design approach for preparation and structure-activity studies of Abeta Oligomerization inhibitors. We[unreadable] will focus our efforts on inhibitors of early Abeta(1-42) oligomers termed "paranuclei." We choose early[unreadable] Abeta(1-42) oligomers as our primary target because Abeta(1-42) is particularly linked to AD and because[unreadable] inhibition of early assembly of Abeta(1-42) will alleviate the neurotoxic effects, both of the oligomers[unreadable] themselves and of the larger neurotoxic assemblies, protofibrils and fibrils, for which paranuclei are[unreadable] precursors. Our design in based on recent experimental and modeling data that delineate structural[unreadable] features of paranucleus assembly, including primary-quaternary structure relationships and[unreadable] conformation of the C-terminus of Abeta(1-42). This region is responsible directly for the enhanced[unreadable] toxicity and distinct Oligomerization pattern of Abeta(1-42) relative to the more abundant alloform,[unreadable] Abeta(1-40). The inhibitor design process is tightly integrated with the structural and biological projects[unreadable] within the overall Program. The design process not only will benefit from the structural data[unreadable] generated by the Program members, but also will feed back into structural studies and provide[unreadable] further understanding of how particular regions and residues in Abeta interact with each other to form[unreadable] oligomers.